Abnormal hemoglobins come to the attention of this laboratory by virtue of its serving as a reference laboratory for the Michigan region. The structural abnormalities of abnormal hemoglobins are defined and correlated with function and kinetics of synthesis of the molecule. From efforts such as these this laboratory noted a trimodal distribution in the proportion of Hb G alpha Philadelphia in heterozygotes with models at 20, 30, and 40% Hb G. Synthesis of alpha and beta chains is balanced. The hypothesis will be tested that this distribution reflects varying numbers of alpha chain structured loci exclusive of alpha-thalassemia. The alpha/beta ratio of cDNA-DNA nucleic acid hybridizations will be measured for the three phenotypes to measure gene dosage directly. Thus far, these studies show that the gene dosage and restriction enzyme cleavage pattern of persons having 40% Hb G are identical to that of alpha-thalassemia. Therefore, the DNA for the alpha chain gene of such patients will be cloned and the DNA sequence determined. Hb Wayne, an alpha-chain frameshift mutant will also be studied. This mutant comprises only 6% of the alpha-chains of heterozygotes. Using recombinant DNA methods we will determine whether mRNA comprises only 6% of the total alpha-mRNA or the theoretical 25%. This will help to define the nature of the quantitative abnormality.